Lymphoid tissues, like many others, depend upon a balance between cellular input and output in order to maintain homeostasis and prevent proliferation-related disorders. This balance represents an equilibrium between cell division and programmed cell death (PCD). A linkage between cell division and PCD is therefor implicit. The hypothesis put forth in this application is that Bcl-2 interacts with and regulates both processes directly. The mechanisms by which Bcl-2 antagonizes cell death directly are becoming clear. The aims of this application are to characterize the biochemical mechanisms by which Bcl-2 regulates cell cycle and therefore promotes cell survival, and to define the specific protein moieties responsible for these interactions. This will be achieved by characterizing changes in cell cycle regulatory proteins induced by Bcl-2, both during normal cell division and after the induction of PCD; by characterizing the effects of deficiencies in cell cycle regulatory molecules on the inhibition of PCD by Bcl-2; and by the analysis of mutations in distinct Bcl-2 protein motifs. These studies will help to elucidate the relationships between PCD and cell proliferation, as well as providing new finding that are unique to each. The information gained from this project will be important in understanding normal lymphopoiesis and homeostasis, as well as related diseases, such as lymphoid malignancies.